N-Benzyloxycarbonylation of amines in the ionic liquid [TPA][l-Pro] as an efficient reaction medium

Article abstract of DOI:10.1016/j.tetlet.2008.02.108

An efficient method for the N-benzyloxycarbonylation of amines is described. The reaction of amines with Cbz-Cl in the ionic liquid [TPA][l-Pro] afforded the corresponding N-Cbz derivatives in excellent yields. The method is versatile for the preparation

Full text of DOI:10.1016/j.tetlet.2008.02.108

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Tetrahedron Letters 49 (2008) 2607–2610
N-Benzyloxycarbonylation of amines in the ionic liquid
[TPA][L-Pro] as an efficient reaction medium
N. Suryakiran, K. Chinni Mahesh, D. Ramesh, J. Jon Paul Selvam, Y. Venkateswarlu *
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Tarnaka, Hubsiguda, Hyderabad 500 007, Andhra Pradesh, India
Received 30 November 2007; revised 13 February 2008; accepted 16 February 2008
Available online 10 March 2008
Abstract
An efficient method for the N-benzyloxycarbonylation of amines is described. The reaction of amines with Cbz-Cl in the ionic liquid
[TPA][L-Pro] afforded the corresponding N-Cbz derivatives in excellent yields. The method is versatile for the preparation of a wide
variety of N-Cbz derivatives of aliphatic and aromatic amines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Amines; N-Benzyloxycarbonylation; Ionic liquid; [TPA][L-Pro]
The protection and deprotection of amines is very
important in multi-step organic syntheses. Among the
amine protecting groups, the benzyloxycarbonyl (Cbz)
group is a very important and useful functionality.1 The
N-Cbz group is stable in the presence of a wide range of
nucleophiles in alkaline as well as aqueous acidic condi-
tions. It can be easily removed by catalytic hydrogenation
without any side reactions to give the parent amine. In
addition, Cbz also serves as a stable protecting group in
peptide chemistry.2 Limited methods are available for the
conversion of amino groups to N-Cbz derivatives. Among
them, reaction of an aryl/alkyl amine and benzyloxycarb-
onyl chloride (Cbz-Cl) in the presence of 4-(dimethyl-
amino)pyridine (DMAP) is the most commonly employed
method.1 Recently, La(NO3)3Á6H2O,3 LiHMDS in THF–
HMPA,4 and b-cyclodextrin in aqueous medium5 have
been reported for this transformation. However, the utility
of a catalyst-free ionic liquid for the preparation of N-Cbz
derivatives has not been investigated at all.
able importance due to their solvating ability, negligible
vapour pressure, easy recyclability and reusability.6–8
Maschmeyer and co-workers9 reported the synthesis of
ionic liquids using quaternary ammonium hydroxide and
chiral carboxylic acids. These salts are promising additives
as different alkyl residues in the (R4N)+ ammonium cation
lead to different charge densities and hydrophobicity.
Recently, we reported the facile synthesis of b-keto-sulf-
ones using tetrapropylammonium L-prolinate [TPA][L-Pro]
as an efficient reaction medium.10,11 In continuation of
our efforts to develop new organic transformations,12–19
we observed that at room temperature, [TPA][L-Pro] is as
an efficient reaction medium for the N-benzyloxycarbonyl-
ation of amines with Cbz-Cl.
Herein, we describe an efficient and high yielding
protocol for the N-benzyloxycarbonylation of amines
(Scheme 1). We prepared11 the ionic liquid tetrapropyl-
ammonium L-prolinate [TPA][L-Pro] from readily available
tetrapropylammonium hydroxide and L-proline in aqueous
In recent years, the use of ionic liquids (ILs) as green sol-
vents in organic synthetic processes has gained consider-
[TPA][L-Pro]
R-NH2
R-NH-Cbz
_
Cbz Cl, rt
*
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
Scheme 1.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.108

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N. Suryakiran et al. / Tetrahedron Letters 49 (2008) 2607–2610
Table 1
N-Benzyloxycarbonylation of amines in the ionic liquid [TPA][L-Pro]
Entry
1
Substrate
Producta
Time (min)
2
Yieldb (%)
95
NH2
NHCbz
NH2
NH2
NHCbz
2
3
5
5
95
93
HO
HO
NHCbz
Me
Me
OMe
OMe
NH2
NHCbz
4
5
95
NH2
NHCbz
NCbz
5
6
5
5
93
90
F
F
F
F
NH2
F
F
NH2
NHCbz
NHCbz
7
5
90
8
9
2
5
92
92
NH2
O
O
NH
NCbz
NH2
NHCbz
10
11
2
93
95
OH
OH
10
NH
NCbz
O
12
5
95
O
NHCbz
NH2

N. Suryakiran et al. / Tetrahedron Letters 49 (2008) 2607–2610
2609
Table 1 (continued)
Entry
Substrate
Producta
Time (min)
Yieldb (%)
O
NH2
O
NHCbz
13
14
5
94
96
HO
HO
2
5
NH2
NHCbz
NH2
NHCbz
O
15
90
95
O
N
O
O
NCbz
NH
N
MeO
MeO
16
10
N
N
N
N
Ts
Ts
a
Products were characterized by 1H NMR and EIMS spectral data.
Isolated yields after column chromatography.
b
medium at 60 °C. In general, all the reactions were carried
out by the addition of the amines (1 mmol) to Cbz-Cl
(1.2 mmol) in [TPA][L-Pro] at room temperature to give
the corresponding N-benzyloxycarbamates in excellent
yields (90–96%, Table 1). The time required for the reaction
was comparatively short (2–10 min). Only the amino
groups were protected while OH groups remained intact,
for example, 4-aminophenol (entry 2), 3-amino propanol
(entry 10) and 4-amino butanol (entry 14). In a chemo-
selective experiment, a 1:1 mixture of an aliphatic amine
(benzyl amine) and an aromatic amine (aniline) (1 mmol
each) was reacted with Cbz-Cl (1 mmol) in the presence
of [TPA][L-Pro]. Only the aliphatic amine was derivatized
and the aromatic amine was left intact. Further, aromatic
amines containing electron-withdrawing groups also gave
the desired derivatives in good yields. Labile functional-
ities such as acetonide protected 1,2-diols were compatible
in this conversion. The protocol is highly chemoselective,
involves simple experimental procedures, mild reaction
conditions and gives excellent yields of Cbz-protected
amines. We believe that the IL polarizes the carbonyl
group of Cbz-Cl and facilitates the reaction (Scheme 2).
In conclusion, we have described an efficient method for
the protection of amines as their N-benzyloxycarbonyl
derivatives in the ionic liquid [TPA][L-Pro] at room temper-
ature in excellent yields. The method has advantages of
reduced reaction time and simple experimental work-up
making it a useful addition to existing methodologies.
Typical experimental procedure: A mixture of amine
(1 mmol) and benzyloxycarbonyl chloride (Cbz-Cl)
(1.2 mmol) was taken in the ionic liquid [TPA][L-Pro]
(1 mL) and the reaction was stirred at room temperature
for the appropriate amount of time (Table 1). After com-
pletion of the reaction as monitored by TLC, water
(5 mL) was added. The product was extracted into ethyl
acetate (3 Â 20 mL) and the combined organic layer was
washed with saturated sodium bicarbonate followed by
brine, and then dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give a crude
product, which was further purified by silica gel column
chromatography. The ionic liquid was recovered from the
aqueous layer by removing the water under reduced pres-
sure or freeze dried and reused without loss of its activity
for the next run.
+
O N
+
4
+
-
NH
O
+
O N
O
4
NH
..
NH2
-
O
O
O
O
Ph
O
Ph
R
N
+
R
+
H
O
Ph
NH2
R
HCl
Scheme 2. A Plausible mechanism.

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N. Suryakiran et al. / Tetrahedron Letters 49 (2008) 2607–2610
6. Fukumoto, K.; Yoshizawa, M.; Ohno, H. J. Am. Chem. Soc. 2005,
Acknowledgements
127, 2398.
7. Fukumoto, K.; Ohno, H. Chem. Commun. 2006, 3081.
8. Wang, C.; Guo, L.; Li, H.; Wang, Y.; Weng, J.; Wu, L. Green Chem.
2006, 8, 603.
9. Allen, C. R.; Richard, P. L.; Ward, A. J.; van de Water, L. G. A.;
Masters, A. F.; Maschmeyer, T. Tetrahedron Lett. 2006, 47, 7367.
10. The ionic liquid [TPA][L-Pro] can be prepared from recemic proline,
which gives same results as from L-proline.
11. Suryakiran, N.; Prabhakar, P.; Rajesh, K.; Suresh, V.; Ven-
kateswarlu, Y. J. Mol. Catal. A: Chem. 2007, 270, 201.
12. Prabhakar, P.; Suryakiran, N.; Venkateswarlu, Y. Chem. Lett. 2007,
36, 732.
13. Srikanth Reddy, T.; Ravinder, K.; Suryakiran, N.; Narasimhulu, M.;
Mahesh, K. C.; Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 2341.
14. Malla Reddy, S.; Venkateswarlu, Y. Tetrahedron Lett. 2005, 46,
7439.
The authors thank CSIR, MoES and DBT, New Delhi,
India, respectively, for the financial support and the Direc-
tor of the Indian Institute of Chemical Technology, for his
encouragement.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
02.108.
References and notes
15. Narasimhulu, M.; Mahesh, K. C.; Srikanth Reddy, T.; Rajesh, K.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 4381.
16. Srikanth Reddy, T.; Narasimhulu, M.; Suryakiran, N.; Mahesh, K.
C.; Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 6825.
17. Narasimhulu, M.; Srikanth Reddy, T.; Mahesh, K. C.; Malla Reddy,
S.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2007, 264, 288.
18. Suryakiran, N.; Rajesh, K.; Prabhakar, P.; Jon Paul Selvam, J.;
Venkateswarlu, Y. Catal. Commun. 2007, 8, 1635.
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999.
2. Reagents in Organic Synthesis; Fieser, L. F., Fieser, M., Eds.; John
Wiley & Sons: New York, 1967; Vol. 1, p 109.
3. Chinni Mahesh, K.; Narasimhulu, M.; Srikanth Reddy, T.; Surya-
kiran, N.; Venkateswarlu, Y. Tetrahedron Lett. 2007, 48, 55.
4. Hernandez, J. N.; Martin, V. S. J. Org. Chem. 2004, 69, 3590.
5. Pavan Kumar, V.; Somi Reddy, M.; Narender, K.; Rama Rao, K.
Tetrahedron Lett. 2006, 47, 6393.
19. Suryakiran, N.; Prabhakar, P.; Srikanth Reddy, T.; Rajesh, K.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 8039.